Sedative but not anxiolytic properties of benzodiazepines ave mediated by the GABAA receptor α1 subtype

被引：768

作者：

McKernan, RM ^{[1
]}

Rosahl, TW ^{[1
]}

Reynolds, DS ^{[1
]}

Sur, C ^{[1
]}

Wafford, KA ^{[1
]}

Atack, JR ^{[1
]}

Farrar, S ^{[1
]}

Myers, J ^{[1
]}

Cook, G ^{[1
]}

Ferris, P ^{[1
]}

Garrett, L ^{[1
]}

Bristow, L ^{[1
]}

Marshall, G ^{[1
]}

Macaulay, A ^{[1
]}

Brown, N ^{[1
]}

Howell, O ^{[1
]}

Moore, KW ^{[1
]}

Carling, RW ^{[1
]}

Street, LJ ^{[1
]}

Castro, JL ^{[1
]}

Ragan, CI ^{[1
]}

Dawson, GR ^{[1
]}

Whiting, PJ ^{[1
]}

机构：

[1] Merck Sharp & Dohme Ltd, Res Labs, Neurosci Res Ctr, Harlow CM20 2QR, Essex, England

来源：

NATURE NEUROSCIENCE | 2000年 / 3卷 / 06期

关键词：

D O I：

10.1038/75761

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

GInhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha(1) H101R) with a diazepam-insensitive alpha(1) subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha(1) subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.

引用

页码：587 / 592

页数：6

共 34 条

[21] Benzodiazepine actions mediated by specific γ-aminobutyric acidA receptor subtypes
Rudolph, U
Crestani, F
Benke, D
Brünig, I
Benson, JA
Fritschy, JM
Martin, JR
Bluethmann, H
Möhler, H
[J]. NATURE, 1999, 401 (6755) : 796 - 800
[22] SAUER B, 1993, METHOD ENZYMOL, V225, P890
[23] A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells
Schwenk, F
Baron, U
Rajewsky, K
[J]. NUCLEIC ACIDS RESEARCH, 1995, 23 (24) : 5080 - 5081
[24] SIEGHART W, 1995, PHARMACOL REV, V47, P181
[25] TARGETED DISRUPTION OF THE C-SRC PROTOONCOGENE LEADS TO OSTEOPETROSIS IN MICE
SORIANO, P
MONTGOMERY, C
GESKE, R
BRADLEY, A
[J]. CELL, 1991, 64 (04) : 693 - 702
[26] Preferential coassembly of α4 and δ subunits of the γ-aminobutyric acidA receptor in rat thalamus
Sur, C
Farrar, SJ
Kerby, J
Whiting, PJ
Atack, JR
McKernan, RM
[J]. MOLECULAR PHARMACOLOGY, 1999, 56 (01) : 110 - 115
[27] Autoradiographic localization of α5 subunit-containing GABAA receptors in rat brain
Sur, C
Fresu, L
Howell, O
McKernan, RM
Atack, JR
[J]. BRAIN RESEARCH, 1999, 822 (1-2) : 265 - 270
[28] ANIMAL-MODELS FOR THE STUDY OF ANTI-ANXIETY AGENTS - A REVIEW
TREIT, D
[J]. NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS, 1985, 9 (02) : 203 - 222
[29] Whiting PJ, 1997, J NEUROSCI, V17, P5027
[30] WIELAND HA, 1992, J BIOL CHEM, V267, P1426

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